Cooperativity of the MUC1 oncoprotein and STAT1 pathway in poor prognosis human breast cancer.

Abstract

Signal transducer and activator of transcription 1 (STAT1) is activated in the inflammatory response to interferons. The MUC1 oncoprotein is overexpressed in human breast cancers. Analysis of genes differentially expressed in MUC1-transformed cells has identified a network linking MUC1 and STAT1 that is associated with cellular growth and inflammation. The results further show that the MUC1-C subunit associates with STAT1 in cells and the MUC1-C cytoplasmic domain binds directly to the STAT1 DNA-binding domain. The interaction between MUC1-C and STAT1 is inducible by IFNgamma in non-malignant epithelial cells and constitutive in breast cancer cells. Moreover, the MUC1-STAT1 interaction contributes to the activation of STAT1 target genes, including MUC1 itself. Analysis of two independent databases showed that MUC1 and STAT1 are coexpressed in about 15% of primary human breast tumors. Coexpression of MUC1 and the STAT1 pathway was found to be significantly associated with decreased recurrence-free and overall survival. These findings indicate that (i) MUC1 and STAT1 function in an auto-inductive loop, and (ii) activation of both MUC1 and the STAT1 pathway in breast tumors confers a poor prognosis for patients.

• Authors: N Khodarev, R Ahmad, H Rajabi, S Pitroda, T Kufe, C McClary, M D Joshi, D MacDermed, R Weichselbaum, D Kufe
• Journal: Oncogene (Oncogene) Vol. 29 Issue 6 Pg. 920-9 (Feb 11 2010) ISSN: 1476-5594 [Electronic] England
• PMID: 19915608 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• MUC1 protein, human
• Mucin-1
• STAT1 Transcription Factor
• Interferon-gamma

Topics

• Amino Acid Sequence
• Animals
• Breast Neoplasms (diagnosis, genetics, metabolism, pathology)
• Cell Line, Tumor
• Cytoplasm (metabolism)
• Female
• Gene Expression Regulation, Neoplastic
• Gene Regulatory Networks
• Humans
• Interferon-gamma (pharmacology)
• Mammary Glands, Human (drug effects, metabolism, pathology)
• Mice
• Molecular Sequence Data
• Mucin-1 (chemistry, genetics, metabolism)
• Prognosis
• Promoter Regions, Genetic (genetics)
• Protein Structure, Tertiary
• Rats
• STAT1 Transcription Factor (genetics, metabolism)
• Signal Transduction (drug effects)